(R)-Cocaine or (-)-cocaine (1) is a plant alkaloid purified from the leaves of Erythroxylon coca and has been a subject of scientific investigation since the late 1800s. It is one of the eight possible stereoisomeric forms of methyl 3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate. ##STR2##
In both animals and humans, cocaine is one of the most reinforcing drugs known, which has given rise to a serious cocaine abuse epidemic in the United States over the last 10-15 years. See, D. F. Musto, Opium, Cocaine and Marijuana in American History, Sci. Amer., 256, 40 (1991); D. Clouet et al., eds., "Mechanisms of Cocaine Abuse and Toxicity," NIDA Research Monograph (1988) at page 88; C. E. Johanson et al., Pharmacol. Rev., 41, 3 (1989).
Cocaine has many physiological effects. It is a local anesthetic, and this property is responsible for its early legitimate use in medicine. However, many newer compounds have been developed that are superior to cocaine for this purpose. Cocaine is also a powerful vasoconstrictant and as such has some current use in medicine during nasal or throat surgery where control of bleeding is desired. Cocaine also has very potent effects on the sympathetic nervous system, and it is well know to increase heart rate and blood pressure. From the point of view of drug abuse, the most relevant effects of the drug include its ability to produce euphoria and its reinforcing documented in human subjects. See, R. R. Griffiths et al., in Advances in Substance Abuse, Vol. 1, N. K. Mello, ed., UAI Press Inc., Greenwich, CT (1980) at pages 1-90. In addition to being a powerful reinforcer, cocaine also has properties common to other drugs subject to abuse. For example, tolerance occurs to some of its effects, and its psychological withdrawal syndrome takes place over a long time period, which includes periods of craving during which relapse to drug use may often occur. See, F. H. Gawin et al., Arch. Gen. Psychiatry, 43, 107 (1986).
Over the past 10 years, there have been significant advances in understanding the mechanism of action of cocaine. The development of drug self-administration as a useful animal model for reinforcing properties has led to exploration of many of the physiological, neurochemical, neuroanatomical, and pharmacological correlates. See, R. R. Griffiths, cited above.
Several studies have shown that cocaine binds to the dopamine transporter and inhibits dopamine transport (M. J. Kubar et al., in "Mechanisms of Cocaine Abuse and Toxicity", D. Clouet et al., eds., NIDA Research Monograph (1988) at pages 14-22). In addition, drugs that are potent in maintaining self-administration such as nomifensine, methylphendiate and mazindol, are also potent inhibitors of binding at the transport site for dopamine, whereas compounds that are weak in self-administration studies are correspondingly weak inhibitors of the binding site. For example, M. C. Ritz et al., in Science, 237, 1249 (1987), showed that the relative ability of several compounds to displace [.sup.3 H]mazindol binding to the dopamine transporter from rat striatum was correlated to drug self-administration studies in nonhuman primates. Similarly, J. Berman et al., J. Pharmacol. Exp. Ther., 251, 150 (1989), found a good correlation between displacement of [.sup.3 H]-cocaine binding to the transporter and drug self-administration behavior in squirrel monkeys. The most potent compounds in binding and behavioral studies reported from both investigations were 3.beta.-phenyltropane-2.beta.-carboxylic acid methyl ester (1a, WIN-35,065-2) and 3.beta.-(p-fluorophenyl)tropane-2.beta.-carboxylic acid methyl ether (1b WIN35,428), the so-called "WIN compounds" reported originally by R. L. Clark et al., J. Med. Chem., 16, 1260 (1973). ##STR3##
Only a limited number of cocaine analogs have been available to study the structural requirements for binding to the dopamine transporter and for cocaine-like reinforcing properties. For example, F. I. Carroll et al., J. Med. Chem., 34, 2719 (Sept. 1991); Eur. J. Pharm., 184, 329 (1990) synthesized and measured the binding affinity of a number of new 3.beta.-(p-substituted phenyl)tropane-2.beta.-carboxylic acid methyl esters, and measured their ability to inhibit the binding of 0.5 nM [.sup.3 H]-1b to the dopamine transport site of rat striata. Compound 1c, X=I was found to have a potency 78 times greater than (-)-cocaine (1), while compound 1d (X=Cl) had a potency 85 times that of cocaine in this in vitro assay. F. I. Carroll et al., in J. Med. Chem., 35, 969 (1992) went on to propose that specific hydrogen bond donor groups are present within the cocaine recognition site which bind to the 2-carbomethoxy group.
However, a need exists for analogs of cocaine that exhibit enhanced analgesic and/or vasoconstrictive properties, and which are potentially more selective than (-)-cocaine. A further need exists for cocaine analogs which can be employed to further characterize the cocaine binding site(s), to assist the development of specific cocaine binding site agonists and antagonists.